α-actinin-4 and CLP36 protein deficiencies contribute to podocyte defects in multiple human glomerulopathies

Zhongmin Liu, Simone Monika Blattner, Yizeng Tu, Robert Tisherman, James H. Wang, Maria Pia Rastaldi, Matthias Kretzler, Chuanyue Wu

Research output: Contribution to journalArticle

Abstract

Genetic alterations of α-actinin-4 can cause podocyte injury through multiple mechanisms. Although a mechanism involving gain-of-α-actinin-4 function was well described and is responsible for a dominantly inherited form of human focal segmental glomerulosclerosis (FSGS), evidence supporting mechanisms involving loss-of-α-actinin-4 function in human glomerular diseases remains elusive. Here we show that α-actinin-4 deficiency occurs in multiple human primary glomerulopathies including sporadic FSGS, minimal change disease, and IgA nephropathy. Furthermore, we identify a close correlation between the levels of α-actinin-4 and CLP36, which form a complex in normal podocytes, in human glomerular diseases. siRNA-mediated depletion of α-actinin-4 in human podocytes resulted in a marked reduction of the CLP36 level. Additionally, two FSGS-associated α-actinin-4 mutations (R310Q and Q348R) inhibited the complex formation between α-actinin-4 and CLP36. Inhibition of the α-actinin-4-CLP36 complex, like loss of α-actinin-4, markedly reduced the level of CLP36 in podocytes. Finally, reduction of the CLP36 level or disruption of the α-actinin-4-CLP36 complex significantly inhibited RhoA activity and generation of traction force in podocytes. Our studies reveal a critical role of the α-actinin-4-CLP36 complex in podocytes and provide an explanation as to how α-actinin-4 deficiency or mutations found in human patients could contribute to podocyte defects and glomerular failure through a lossof-function mechanism.

Original languageEnglish
Pages (from-to)30795-30805
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number35
DOIs
Publication statusPublished - Sep 2 2011

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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